Drug Design, Development and Therapy
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Dapagliflozin for the treatment of type 2 diabetes:
a review of the literature
Mujahid A Saeed 1
Parth Narendran 2
1
Department of Diabetes, University
Hospital Birmingham NHS Foundation
Trust, 2School of Clinical and
Experimental Medicine, University
of Birmingham, Birmingham, UK
Correspondence: Mujahid Saeed
Department of Diabetes, Fifth floor,
Diabetes Centre, Nuffield House,
University Hospitals Birmingham NHS
Foundation Trust, Queen Elizabeth
Hospital Birmingham, Mindelsohn Way,
Edgbaston, Birmingham, West Midlands
B15 2WB, UK
Email mujahid.saeed@uhb.nhs.uk
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http://dx.doi.org/10.2147/DDDT.S50963
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Objective: Dapagliflozin was the first drug in a class of therapies that took a new approach to
glycemic control in adults with type 2 diabetes (T2D). It is an inhibitor of the sodium glucose
cotransporter, resident in the proximal nephron, which is responsible for the recovery of filtered
glucose back into circulation. Inhibiting this cotransporter reduces glucose recovery, increases
glucose excretion, and reduces hyperglycemia. Here, we review some of the literature relating
to the action, efficacy, and clinical use of dapagliflozin.
Materials and methods: A Medline search was conducted within date, animal, and lan-
guage limits, and relevant papers were selected for review. Conference proceedings were
reviewed to obtain up-to-date literature on this drug. Clinical trial websites were reviewed
for ongoing studies.
Results: On average, treatment with dapagliflozin results in improvement in glycated
hemoglobin by 0.50%, fasting plasma glucose by 1 mmol/L, weight by 2 kg, body mass index
by 1.1%, and systolic/diastolic blood pressure by 4/2 mmHg over 24–52 weeks. The weight
benefit is greater when used in association with sulfonylureas. It is generally well tolerated,
but comes with an increased risk of genitourinary and urinary tract infections. In addition, it is
associated with reversible changes to renal function that need to be explored. Early reports of
an association with cancer also need to be carefully monitored.
Conclusion: Dapagliflozin is a useful therapy for adult patients with T2D. It also holds potential
for a broader range of patients with T2D (such as the elderly and pediatric populations), as well
as those with other forms of diabetes, such as type 1 diabetes. While longer-term outcome stud-
ies of safety and efficacy are awaited, dapagliflozin forms a very useful and welcome addition
to our armamentarium for managing patients with T2D.
Keywords: diabetes, dapagliflozin, SGLT2, SGLT2 inhibitor, review
Introduction
Diabetes is a significant international health care problem. There are currently
382 million people with diabetes, a staggering 8.3% or one in 12 of the adult popula-
tion. This figure is estimated to rise to 592 million people by 2035.1 The disease comes
with a financial burden. An estimated US$548 billion was spent on this condition in
2013. The vast majority of this cost relates to the management of diabetic complica-
tions. These complications include renal replacement therapy, cardiovascular disease,
diabetic retinopathy, and diabetic foot disease.
Optimized glucose control reduces the risk of diabetic complications.2,3 Several
glycated hemoglobin (HbA1c) glycemic targets have been proposed for the manage-
ment of diabetes, ranging from 6.0% to 8.5% (42–69 mmol/mol).4–10 While the last
few years have seen an improvement in glucose control and generally in diabetes care,
significant further improvement is urgently required. It is estimated that only about
half of the diabetic population reach the proposed glycemic targets.11 Reasons for
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failure are complex, but there is little doubt that identifying
the right therapy for the patient will go some way to improve
their glycemic control.
A number of factors need to be considered when indi-
vidualizing first-line therapy. These are outlined in Table 1.
Tolerability and side effects in particular significantly con-
tribute to noncompliance and therapy failure. It is therefore
important to have access to a range of therapies that can be
trialed for individual patients.
Furthermore, type 2 diabetes (T2D) is a progressive condi-
tion with a gradual and continuing loss of β-cell function.13,14
This results in deterioration in glycemic control and eventually
for the need for insulin-replacement therapy.15 This long-term
requirement for the escalation of therapy provides additional
pressure to have access to a range of therapies. Additionally,
excess adiposity is seen in most T2D patients16 and is associ-
ated with insulin resistance,17 and targeting it is an important
consideration in diabetes management.
The twenty-first century has seen the emergence of sev-
eral new classes of antidiabetic drugs. One is the sodium
glucose cotransporter (SGLT)-2 inhibitors. Dapagliflozin
is the first in this class of new therapies. It is currently
licensed by the US Food and Drug Administration (FDA;
in January 2014),18 the Committee for Medicinal Products
for Human Use of the European Medicines Agency (EMA;
in April 2012)19 and the Medicines and Healthcare Prod-
ucts Regulatory Agency in the UK, the Ministry of Health,
Labour, and Welfare (MHLW) in Japan (March 2014),20 and
by the Scottish Medicines Consortium (in January 2013).21
The aim of this article is to review the literature on dapa-
gliflozin with regard to its mechanism of action, efficacy, side
Table 1 Some factors to consider while managing patients with
diabetes
Factors Considerations
Age Licensed indications (eg, dapagliflozin licensed for
use in patients 18–75 years of age)
Weight Weight-neutral or promotion of weight loss in
overweight/obese patients
Pregnancy Contraindications exist for most oral
hypoglycemic agents
Renal/hepatic Metabolism of the drug and/or route of excretion
dysfunction
Ease of use Frequency and timing of medication
Polypharmacy This can lead to poor patient adherence12
Occupation HGV drivers and the risk of hypoglycemia
Costs Individual, national, or insurance costs can dictate
medication choice
Side effects Hypoglycemia, weight gain, gastrointestinal
disturbance, edema, etc
Abbreviation: HGV, heavy goods vehicle.
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effects, drug interaction, contraindications, and cost. We also
review its place in the treatment of T2D.
Materials and methods
An Ovid Medline (1946 to September 2014) search was
carried out using the terms “diabetes” and “dapagliflozin”.
Papers and abstracts on animal studies and not in English
were excluded, including any duplicates (Figure 1). Any
useful references cited in these papers/abstracts were also
reviewed. A search on ClinicalTrials.gov using the search
term “dapagliflozin” was also made to find information on
past and ongoing studies. Other sources included the World
Health Organization, the FDA, Centers for Disease Control
and Prevention, clinical guidelines (including National Insti-
tute for Health and Care Excellence technology appraisal),
FDA/EMA/UK labeling of summary of product characteris-
tics, briefings, press releases, and Google searches. Confer-
ence abstracts were also used.
Mechanism of action
The human nephron reabsorbs almost all of the glucose pres-
ent in the filtrate, and can do so from as early as 34 weeks of
gestation.22,23 This comprises 180 g of glucose per day.24,25
Only 1% of the filtered glucose makes its way into the urine,
and 90% of the filtered glucose is reabsorbed by SGLT2
expressed by epithelial cells lining the first segment of the
proximal convoluted tubule. The remaining 10% is reab-
sorbed by SGLT1 lower in the nephron.26,27
The process of glucose reabsorbtion28–31 starts at the lumi-
nal surface of the proximal tubular epithelium, where SGLT2
actively moves glucose from the glomerular filtrate into
the epithelial cells (Figure 2). The cotransporters move
glucose along with sodium, which is in turn driven by the
active transport of sodium out of the basolateral cells by the
Na+/K+-adenosine triphosphatase pump. Glucose transport-
ers (GLUTs) are passive transporters that move glucose out
of the cell across the basolateral membrane. This happens
along the concentration gradient. This entire process results
in glucose being moved from the proximal tubule back into
the circulation.
Two genetic disorders23 have helped our understanding
of the working of the SGLT2/GLUT2 transporter molecules:
familial renal glycosuria and Fanconi–Bickel syndrome.
Familial renal glycosuria
This autosomal-recessive condition occurs due to mutations
in the SLC5A2 gene, which encodes SGLT2. Persistent glyco-
suria is present, but without significant disturbance in plasma
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Dovepress Dapagliflozin for T2D

Ovid Medline search

(1946–September 2014) 158 papers found
"dapagliflozin" and "diabetes"

10 duplicates
excluded

3 non-dapagliflozin
studies excluded

10 non-English
papers excluded

13 animal studies
excluded

122 papers included

Figure 1 Flow diagram of search process.

GLUT2
Basolateral membrane

Lumen Blood
SGLT2
Luminal membrane

Na+-K+
ATPase

Cell

Key: Glucose ( ) Potassium ( ) Sodium ( )

Figure 2 S1 segment of the promixal convoluted tubule of the nephron.

Notes: SGLT2 located on the luminal membrane of the S1 segment of the proximal convoluted tubule of the nephron actively transports glucose from the lumen into the
cell against a concentration gradient. The glucose is then transported out through the basolateral side via GLUT2. Na+-K+ ATPase actively excretes sodium from the cell in
exchange for potassium.
Abbreviations: SGLT, sodium glucose cotransporter; GLUT, glucose cotransporter; ATPase, adenosine triphosphatase.

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Saeed and Narendran
glucose, glucose tolerance, or insulin. This is considered to
be a benign condition, and urinary tract infections are only
occasionally seen in severe forms of this condition.32
Fanconi–Bickel syndrome
This is a rare autosomal condition characterized by a mutation
in the SLC2A2 gene, which encodes the GLUT2 transporter,
and which results in glycosuria.33
Phlorizin,30,34 first isolated from the root bark of the apple
tree in 1835, is an inhibitor of SGLTs. However, this was not
used therapeutically due to its nonspecificity for SGLT2. The
use of this drug resulted in blockade of intestinal SGLT1,
poor intestinal absorption of glucose, and thus led to diarrhea
and dehydration. Dapagliflozin, however, is a highly selec-
tive competitive and reversible inhibitor of SGLT2,35 and
can achieve increased urinary excretion of glucose without
the gastrointestinal side effects associated with nonspecific
SGLT therapy.
While the mechanism of action of dapagliflozin is primar-
ily through SGLT2 blockade, this may be complicated by the
concurrent secretion of glucagon. Recent data36 indicate that
SGLT2 is also expressed in human pancreatic α-cells, and
therapy with dapagliflozin is described to increase circulating
glucagon.37 This increased glucagon potentially dampens the
efficacy of SGLT2 inhibitors and needs further examination.
This potentially is also protective against hypoglycemia.
Pharmacokinetics
Dapagliflozin (Figure 3) is rapidly and well absorbed after
oral administration.38,39 Maximum dapagliflozin plasma
concentrations occur within 2 hours of administration (in the
fasted state). Bioavailability is 78% with the 10 mg once-
daily (OD) dosing. It can be taken with or without food.40
It is 91% protein-bound, and this is not affected by hepatic
or renal disease.
Dapagliflozin is metabolized to its inactive metabolite –
dapagliflozin 3-O-glucuronide – in the liver and kidney by
the enzyme uridine diphosphate-glucuronosyltransferase
1A9. The mean plasma terminal half-life for dapagliflozin is
13 hours (10 mg dosing). Dapagliflozin and its metabolites are
mainly excreted via the urine, and the excretion is impaired in
OH
CI O CH3
HO O Dual therapy
HO
OH
Figure 3 Chemical structure of dapagliflozin.
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the presence of renal disease;41 15% is excreted unaltered via
the feces and 2% excreted unaltered via the urine.
There do not appear to be any ethnic variations in the
pharmacokinetics or pharmacodynamics of dapagliflozin,
though to date this has only been examined in studies in
Chinese42 and Japanese43 populations.
Pharmacodynamics
Dapagliflozin is associated with dose-dependent glycosuria
and increased diuresis averaging 375 mL/day.38,39,44,45 There
is a transient increase in urinary sodium excretion, but this
does not appear to affect serum sodium. There is a transient
increase in urinary uric acid excretion, but a sustained reduc-
tion in serum uric acid levels. The mechanism of reduced
serum uric acid levels is unclear, but was recently proposed to
be due to glycosuria-induced uric acid secretion via GLUT9
isoform 2 in the proximal tubule or inhibition of uric acid
uptake at the collecting duct of the renal tubule.46 Addition-
ally, this could be due to the weight reduction associated
with dapagliflozin.
Place in management
Dapagliflozin can be used as monotherapy or in combina-
tion with other oral hypoglycemic agents and insulin.47
It can be used at any stage of the natural history of T2D.48
It has now been placed within clinical guidelines8 as mono-
therapy and in combination therapy where the renal func-
tion is not chronic kidney disease (CKD) stage 3 or lower
(,60 mL/min/1.73 m2).
While studies have used various doses of dapagliflozin,
for the purposes of this review we only report the results
of the 5 and 10 mg doses, because only these are currently
licensed for therapy.
Monotherapy
Dapagliflozin has been studied as a monotherapy against
placebo49–53 and versus metformin or placebo.54 In these
studies, the mean HbA1c reduction compared to placebo
at 24 weeks was 0.66–1.45%, and weight reduction was
1.0–2.73 kg. There was a reduction in fasting glucose, and
more patients achieved an HbA1c ,7% in at least one study.
Genital and urinary infections are more common (3.7% and
2.3% difference, respectively) compared to placebo.53
In dual therapy, dapagliflozin has been studied (against placebo)
with metformin,55–60 metformin slow/extended release,51,54
glimepiride,61,62 pioglitazone,63 sitagliptin,64 and exenatide.65
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The highest reduction in HbA1c was seen when dapagliflozin
was combined with metformin. Here, HbA1c reduced by 0.8%
following 102 weeks of therapy,56 compared to 0.5%–0.68%
when combined with the other agents. The highest reduction
in weight was seen when combined with sulfonylureas (SUs).
When combined with glipizide, an average 4.4 kg in weight
was lost compared to glipizide alone.58–60 In comparison, weight
loss of 1.74 kg with metformin56 and 1.8 kg with sitagliptin
has been reported.64 Across all studies, a 5%–10% increase in
genital infections was reported. There are no human studies of
dapagliflozin with glucagon-like peptide-1 analog therapy.
Triple therapy
Dapagliflozin has been used with metformin and sitagliptin,64,66
metformin and saxagliptin,67 and metformin and an SU,68 in
triple combinations. HbA1c reduction of up to 0.6% and
body weight reductions of 2.2 kg were reported. Genital
and urinary infections were higher than in control groups.60
With insulin
A number of studies of dapagliflozin in combination with
insulin have been undertaken, and a further study is ongoing
(ClinicalTrials.gov identifier: NCT02096705). Studies to date
demonstrate benefits in HbA1c (-0.4%), weight (-3.33 kg),
along with a stable insulin dose (-19.2 units when compared
to increased requirements in the placebo group) at 104 weeks.
Increased hypoglycemia rates were noted at 48 weeks, which
leveled out by 104 weeks. There were higher rates of genital
and urinary infections.69–71
Meta-analyses of dapagliflozin efficacy
There have been several meta-analyses on dapagliflozin to
date.72–76 They suggest that treatment with dapagliflozin results
in average improvement in HbA1c by 0.50%, fasting plasma
glucose by 1.1 mmol/L, weight by 2 kg (4.5 kg when used with
SUs), body mass index by 1.1%, and systolic/diastolic blood
pressure (BP) by 4/2 mmHg, but is associated with an increased
risk of genitourinary (odds ratio 3.50) and urinary tract (odds
ratio 1.40) infections. These analyses are summarized in
Table 2 and show placebo-subtracted data from randomized
controlled trials. By way of illustration, in one meta-analysis,
study durations ranged between 12 and 104 weeks, with about
4,000 patients randomized across these randomized controlled
trials (n=12).72
Benefits other than glucose
Weight
Weight loss is a benefit of therapy with dapagliflozin. It
is thought to be through fluid loss in the initial phase of
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Dapagliflozin for T2D
treatment, and then a more gradual loss through the net
calorie deficit (typically 200–300 kcal per day). More
recently, it has been shown that dapagliflozin therapy also
reduces fat mass.77,78 Meta-analyses (Table 2) show about a
1–2 kg weight reduction with this agent, and up to 5 kg when
used in combination with SUs.
Hypertension
Investigators have noted a lowering of both systolic and
diastolic BP in patients, and this is thought to be due to a
combination of the diuretic effect of glycosuria, a natriuretic
effect,79 as well as via weight loss. The BP lowering is noted
as early as 1–2 weeks of treatment initiation, and averages 4/2
mmHg.29 The BP-lowering effects of dapagliflozin also mani-
fest in patients on established antihypertensive therapy.80
Sjöström et al81 pooled safety data from 13 placebo-
controlled Phase IIB/III studies, and found a slightly higher
cumulative frequency of orthostatic reactions over 24 weeks
with dapagliflozin (13.1% versus 11.3% with placebo),
although adverse events due to orthostatic hypotension were
rare (0.1%) and not serious.
Lipids
Dapagliflozin 10 mg OD has shown a mean change com-
pared to placebo in total cholesterol of 2.5%, high-density
lipoprotein of 3.3%, low-density lipoprotein of 3.9%, and
triglycerides of -2.0%.38 Meaningful long-term data are
required to understand if this has any clinical impact.
Quality of life
Dapagliflozin-treated patients have been shown to have a
high health-related quality-of-life (HRQOL, EQ-5D) score in
several domains. This persisted for 102 weeks.82 In a triple-
therapy regimen, dapagliflozin showed greater improvement
over placebo in weight change-related QOL, similar obesity-
specific QOL, and greater treatment satisfaction.83
Side effects
Genital (vulvovaginitis and balanitis)
infections
Genital infections are by far the commonest side effect of
dapagliflozin. Pooled data from 12 studies84 suggest infec-
tion rates of 5.7%, 4.8%, and 0.9% of study subjects treated
with dapagliflozin 5 mg (n=1,145), 10 mg (n=1,193), or
placebo (n=1,393), respectively. These were mainly mild
or moderate infections that occurred in the first 6 months
with low risk of recurrence or new emergent infections with
prolonged therapy. Those with a previous history of these
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 Table 2 Meta-analyses of dapagliflozin

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Study Year published RCTs included, n Theme of the meta-analysis Summary
75
Musso et al 2012 13 Efficacy and safety of dapagliflozin – ↓ HbA1c (-0.52%, 95% CI -0.46% to -0.57%; P,0.00001)
– ↓ FPG (-18.28 mg/dL [1.01 mmol/L], 95% CI -20.66 [1.15 mmol/L] to

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-15.89 [0.88 mmol/L]; P,0.00001)
Saeed and Narendran

– ↓ BMI (-1.17%, 95% CI -1.41 to -0.92; P,0.00001)

– ↓ SBP (-4.08 mmHg, 95% CI -4.91 to -3.24)
– ↓ DBP (-1.16 mmHg, 95% CI -1.67 to -0.66)
– ↓ Serum uric acid (-41.50 μmol/L, 95% CI -47.22 to -35.79)
– ↑ Risk genital infections (OR 3.57, 95% CI 2.59–4.93)
– ↑ Risk of UTIs (OR 1.34, 95% CI 1.05–1.71)

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– ↑ Hypoglycemia (mild) when added to insulin (OR 1.27, 95% CI 1.05–1.53)
Vasilakou et al76 2013 –a Efficacy and safety of SGLT2 inhibitors – ↓ HbA1c (-0.59%, 95% CI -0.67% to -0.50% versus placebo)
– ↓ BW (-1.92 kg, 95% CI -2.23% to -1.60%; P,0.00001 versus placebo)
– ↓ SBP/DBP
– ↓ CV events (OR 0.73, 95% CI 0.46–1.16)
– ↑Genital infections (OR 3.48, 95% CI 2.33–5.20 versus placebo; OR 4.81,
95% CI 2.97–7.81 versus active agent)
– ↑ UTIs (OR 1.43, 95% CI 1.05–1.94 versus placebo; OR 1.69,
95% CI 1.19–2.40 versus active agent)
– ↑ Hypoglycemia (OR 1.20, 95% CI 0.88–1.64 versus placebo; OR 0.49,
957% CI 0.18–1.39 versus active agent)
– ↑ Hypotension
Goring et al74 2014 6 Adding dapagliflozin versus other OHAs – Similar efficacy
to metformin monotherapy – Similar or reduced hypoglycemic episodes
(1-year data) – Added benefit of weight reduction (versus DPP-4 inhibitors, -2.74 kg, 95%
CI -5.35 to -0.10); versus SUs, -4.67 kg, 95% CI -7.03 to -2.35)
Sun et al72 2014 12 Synergism of dapagliflozin in – ↓ HbA1c (-0.52%, 95% CI -0.60% to -0.45%; P,0.001)
combination with other OHAs – ↓ FPG (-1.13 mmol/L, 95% CI -1.33 to -0.93; P,0.001)
– ↓ BW (-2.10 kg; 95% CI -2.32 to -1.88; P,0.001)
Zhang et al73 2014 10 Efficacy and safety of dapagliflozin – ↓ HbA1c (-0.53%, 95% CI -0.58% to -0.47%; P,0.00001)
– ↓ FPG (-1.06 mmol/L, 95% CI -1.20 to -0.92; P,0.00001)
– ↓ BW (-1.63 kg, 95% CI -1.83 to -1.43; P,0.00001)
– No hypoglycemia as monotherapy
– ↑ Hypoglycemia (RR 1.16, 95% CI 1.05–1.29; P=0.005) when added to a
hypoglycemic agent
– ↑ Risk of UTIs (RR 1.33, 95% CI 1.10–1.60; P=0.004)
– ↑ Risk of genital infections (RR 3.23, 95% CI 2.50–4.18; P=0.00001)
Note: aSeveral studies used.
Abbreviations: BMI, body mass index; BW, body weight; CI, confidence interval; DBP, diastolic blood pressure; DPP, dipeptidyl peptidase; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; OHAs, oral hypoglycemic agents;
OR, odds ratio; RCTs, randomized controlled trials; RR, relative reduction; SBP, systolic blood pressure; SGLT, sodium glucose cotransporter; SUs, sulfonylureas; UTIs, urinary tract infections.

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infections were at higher risk. These infections responded
to standard oral antibiotic therapy. Therapy discontinua-
tion was rare.
Urinary tract infections
Urinary tract infections have also been reported.85 For
dapagliflozin 5mg, 10 mg, or placebo, urinary tract infec-
tions were reported in 5.7%, 4.3%, and 3.7% of patients,
respectively. Again, these were mild or moderate infections
that responded to standard oral antibiotic therapy. Therapy
discontinuation for this reason was also rare (0.3% with
dapagliflozin and 0.1% with placebo). There was no increase
in serious infections, eg, pyelonephritis.
Hypoglycemia
Hypoglycemia is not associated with dapagliflozin mono-
therapy, nor with dual therapy with metformin. It is associ-
ated with less hypoglycemia than SUs.60 Dapagliflozin is
however associated with an increased risk of hypoglycemia
when used with other hypoglycemic agents, such as insulin
and SUs.73 It is advisable that the dose of these agents are
downtitrated at initiation of dapagliflozin in order to reduce
the risk of hypoglycemia at the onset of therapy.
Dehydration
Volume depletion (dehydration, hypotension, or hypovolemia)
appears uncommon with dapagliflozin therapy. These were
reported at 0.8% versus 0.4% for dapagliflozin 10 mg OD
versus placebo (not statistically significant).
Other side effects
Some common side effects of dapagliflozin include back
pain, dyslipidemia, dizziness, and hematocrit increase.38
Potential for “off-target” effects
that need further monitoring
Renal dysfunction
Mean estimated glomerular filtration rate (GFR) and creati-
nine clearance appear to fall in the first week with dapagli-
flozin therapy, but remain stable thereafter up to 104 weeks
and return back to baseline after 2–6 months, whereas there
is a continual slow decline seen with placebo. The changes
in the first week are felt to be due to the diuretic and antihy-
pertensive effect and a possible enhanced tubuloglomerular
feedback.86,87 The creatinine changes are reversible,88 and
therefore do not appear to demonstrate an irreversible dam-
age to the nephrons.
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Dapagliflozin for T2D
Cancer
The FDA had highlighted increased signals for cancer seen
in early studies.89 These were bladder and breast cancer.
For bladder cancer, there were nine patients on dapagli-
flozin and one on placebo (0.3% versus 0.05%, respec-
tively). All patients were male, and most were aged $60 years.
There was a current or past smoking history in six patients,
and five had microscopic hematuria at baseline from the
dapagliflozin group.
There were nine patients who developed breast cancer
(compared to one in the control group; 0.4% versus 0.1%,
respectively). All were aged over 50 years (seven were over
60 years in age), all diagnoses were made within the first
year of exposure, and two diagnoses were made within the
first 8 weeks of exposure to dapagliflozin.
The duration of exposure to dapagliflozin was too short to
be attributable to these cancers. The cancer risk was subse-
quently reevaluated89 and license-authorized by the FDA.18
The safety of dapagliflozin has been examined in animal
studies and also the effects of dapagliflozin and increased
glucose on human bladder transitional cell carcinoma cell
lines and in vivo xenograft models. There was no increased
cancer with dapagliflozin in either of these models.90 Fur-
thermore, canagliflozin, a comparator medication, has not
shown a higher incidence in these cancers, but this could be
due to different monitoring precautions. However, longer-
term human safety data are awaited.
Dosage
Dapagliflozin is marketed under the trade names of Forxiga®
in the EU91 and in the US as Farxiga®.18 It is available in 5 mg
or 10 mg strengths. It is also available in combination with
metformin, under the trade name of Xigduo®, in 5 mg/850 mg
or 10 mg/850 mg (dapagliflozin/metformin) strengths.92
Contraindications
Age
Due to comorbidities, concurrent medication, and risk of
volume depletion, dapagliflozin is to be used with caution
in the $65-year age group; it is not recommended in those
aged $75 years (Table 3). Barring these considerations, a
placebo-controlled pool of nine double-blind Phase IIB/III
studies shows dapagliflozin is safe and well tolerated in old
patients with T2D up to 104 weeks of studied data.93
Pregnancy
There are no trials to support the use of dapagliflozin
in pregnancy. The manufacturers advise to discontinue
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treatment if pregnancy is detected.38 In rat studies, toxicity

Notes: aSafety data in chronic kidney disease 3A (45–59 mL/min/1.73 m2) is available for both canagliflozin114 and empagliflozin115; bdescribed as “very common” (.1/10 frequency) in canagliflozin versus “common” ($1/100 to ,1/10) in
have a higher incidenceb compared
Vulvovaginal candidiasis appears to

to dapagliflozin and empagliflozin)

to the developing kidney was observed in the time period
corresponding to the second and third trimesters.

Side effects
Use of dapagliflozin in the presence
of renal, liver, and cardiovascular
disease
Renal disease
-

The glycemic benefit of dapagliflozin persists in renal

Severe hepatic impairment
Start at 5 mg OD; if tolerated,

disease at least down to the level of CKD stage 3

($60 mL/min/1.73 m2).87 It has not been tested in patients
with more significant renal disease. Therapy also induces
can use 10 mg OD

weight loss (-1.33 and -1.68 kg for 5 and 10 mg, respec-

tively) and lowers BP. Importantly, there is no further
Do not use

Do not use

deterioration in renal function in these patients. There-

fore, there is potentially some benefit in CKD stage 3A
(45–59 mL/min/1.73 m2) patients, but only of a modest
maintain or reduce to 100 mg OD when already on

nature. Longer-term studies are required.

maintain or reduce to 10 mg OD when already ona
Renal impairment (eGFR: mL/min/1.73 m2)

,60: do not initiate; if eGFR falls to this level,

,60: do not initiate; if eGFR falls to this level,

Liver disease
,45: do not use, and stop when already on

,45: do not use, and stop when already on

T2D is associated with liver disease.94,95 Dapagliflozin has

been tested in patients with varying degrees of liver disease
at a dose of 10 mg. It was well tolerated, and there was no
dapagliflozin and empagliflozin (based on information available in the summary of product characteristics for each drug).

change in liver-function tests.96 In clinical practice, no dos-

,60: not recommended

age modification is necessary with mild or moderate hepatic

impairment. In patients with severe hepatic impairment, a
starting dose of 5 mg is recommended by the manufactur-
ers, and if the medication is well tolerated, the dose may be
increased to 10 mg.38
Table 3 Differentiating features between dapa-/empa-/canagliflozin

Cardiovascular disease
$65: volume depletion should be taken into account

$75: volume depletion should be taken into account

$65: volume depletion should be taken into account

Dapagliflozin has been shown to be safe and efficacious

Abbreviations: eGFR, estimated glomerular filtration rate; OD, once daily.

in a large (964 patients) study of older T2D patients with

coexistent cardiovascular disease.97 Dapagliflozin improved
glycemic control without an increase in hypoglycemia,
promoted weight loss, and was well tolerated in the study
subjects, and these benefits persisted for 2 years.98
Age of patient (years)

$75: not recommended

.85: not recommended

There is an ongoing study (Multicenter Trial to Evaluate

the Effect of Dapagliflozin on the Incidence of Cardiovascu-
lar Events [DECLARE-TIMI58], ClinicalTrials.gov identi-
fier: NCT01730534), further evaluating this subject and due
to end in April 2019.
There is a 20-year simulation study99 estimating the long-
term cardiovascular and microvascular outcomes that found
Empagliflozin
Dapagliflozin

Canagliflozin

relative reductions in the incidence of myocardial infarction,

stroke, cardiovascular death, and all-cause death of 13.8%,
Drug

9.1%, 9.6%, and 5.0%, respectively, and relative reductions in

2500 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2014:8
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Dovepress
the incidence of end-stage renal disease, foot amputation, and
diabetic retinopathy of 18.7%, 13.0%, and 9.8%, respectively,
when compared with standard care, thereby potentially show-
ing additional benefits with adding dapagliflozin to standard
therapy in reducing diabetes-related complications.
Use of dapagliflozin in other
contexts
Ethnicity
Studies have now shown efficacy of dapagliflozin in
Chinese42,53 and Japanese41,43,100 populations. These studies
demonstrated that it is as effective at lowering glucose in
these populations as it is in the white Caucasian population.
There is, however, a need for studies in other ethnicities.
Type 1 diabetes
There is currently one study that has examined dapagliflozin in
type 1 diabetes (T1D). This was a randomized, double-blind,
placebo-controlled, parallel-group, Phase II trial (ClinicalTri-
als.gov identifier: NCT01498185). It was designed to explore
dapagliflozin (1, 2.5, 5, 10 mg OD) as an add-on to insulin
therapy in subjects with T1D. A dose-dependent increase in
urinary glucose and a reduction in glycemic levels/variability
and total daily dose of insulin was noted with dapagliflozin.
Hypoglycemia was noted to be common in all treatment
groups, and led to discontinuation in one patient on dapagli-
flozin 10 mg OD due to a major hypoglycemic event.101
Another gliflozin, empagliflozin, has been studied102 in
an open-label 8-week trial at a dose of 25 mg OD on renal
hyperfiltration in T1D. Patients were divided into those with
renal hyperfiltration (GFR $135 mL/min/1.73m2, n=27) or
normal GFR (GFR 90–134 mL/min/1.73m2, n=13). A sta-
tistically significant reduction in total daily dose of insulin
and in HbA1c was observed in both study groups. There is
therefore proof of concept for the use of SGLT2 inhibitors
for the therapy of T1D.
Drug–drug interactions
Dapagliflozin and loop diuretics are advised not to be used
together, in order to avoid hypotension and dehydration.
Lack of interaction has been shown between dapagliflozin
and simvastatin, valsartan, warfarin, digoxin, rifampin, or
mefenamic acid.103,104
Other considerations
Cost
Dapagliflozin is a cost-effective treatment when used in com-
bination with insulin in patients with T2D. Van Haalen et al105
Drug Design, Development and Therapy 2014:8
Dapagliflozin for T2D
used the Cardiff Diabetes Model to show a lower incidence
of both micro- and macrovascular complications, a greater
life expectancy, and an incremental benefit of 0.42 quality-
adjusted life-years (QALYs). They conclude that the lifetime
incremental cost per patient in those taking dapagliflozin was
€2,293, with a €27,779 incremental cost-effectiveness ratio
per life-year gained and a €5,502 incremental cost-utility
ratio per QALY gained.
Sabale et al106 studied the cost-effectives of dapagliflozin
added to metformin compared to an SU added to metformin
in patients with T2D and inadequate diabetes control.
In this 52-week Scandinavian study, there was a gain in
cost per QALY ranging between €4,769 and €7,944. The
QALY gains for the dapagliflozin group were reported to be
between 0.236 and 0.278, with incremental costs between
€1,125 and €1,962.
In the UK, the National Institute for Health and Care
Excellence has undertaken a technology appraisal (TA288)
to evaluate the cost-effectiveness of dapagliflozin.107
What does the future hold
for the SGLT2 inhibitors?
Competition within this class of drug is proving to be
fierce,108 with several other SGLT2 inhibitors on the market:
canagliflozin, developed by Janssen-Cilag (approved by
the FDA in March 2013 and EMA in November 2013);
empagliflozin, developed by Boehringer Ingelheim and Eli
Lilly (approved by the EMA in March 2014 and the FDA
in August 2014); ipragliflozin,109 developed by Astellas
Pharma and Kotobuki Pharmaceutical (approved by the
MHLW, Japan in January 2014); tofogliflozin,110 devel-
oped by Chugai Pharmaceutical (approved by the MHLW,
Japan in March 2014), and luseogliflozin,111 developed by
Taisho Pharmaceutical (approved by the MHLW, Japan in
March 2014).
There are yet more molecules, including ertugliflozin112
and remogliflozin,113 that have undergone development
through Phase I, II, and III trials, with some, including
remogliflozin, that have been discontinued. While the cur-
rently available SGLT2 inhibitors are broadly similar, there
are some differentiating features (Table 3).
Conclusion
Dapagliflozin is the first class SGLT2 inhibitor licensed for
use in adult patients with T2D. Large studies have demon-
strated glycemic benefit with this therapy without significant
hypoglycemia. There are also benefits with BP, weight, and
lipids that may translate to cardiovascular benefit.
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Saeed and Narendran
However, a number of important clinical questions remain
to be answered, and we require further reassurance on issues
relating to safety. Specifically, we see these as being:
1. the safety profile in patients over the age of 75 years and
in pediatric patients
2. the efficacy profile in estimated GFR ,60 mL/min/1.73 m2,
particularly when other agents have these data already
available
3. the long-term cardiovascular safety and risk-modification
profile
4. cancer safety data, particularly bladder cancer, in view
of the increased glucose load passing through the urinary
system
5. combination use with glucagon-like peptide-1 agonists
6. use in T1D, pregnancy, monogenic forms of diabetes,
and other conditions resulting in hyperglycemia
7. efficacy across different ethnicities.
Regardless, dapagliflozin makes a significant contribu-
tion to the range of therapies we require for the optimal
management of patients with T2D. Its action is not affected
by where a patient lies in the natural history of diabetes and
regardless of residual β-cell function. It is also independent
of the mechanisms through which other oral hypoglycemic
agents work, such as increasing insulin or decreasing gluca-
gon secretion, reducing gluconeogenesis or insulin resistance,
slowing intestinal carbohydrate digestion/absorption, or
increasing glucose deposition into liver, muscle or fat tis-
sues. This allows for a versatile therapy that can be used in
patients who are drug-naïve, as well as those on established
blood glucose-lowering therapy.
Acknowledgment
The authors would like to thank Professor Clifford Bailey
(Aston University, Birmingham, UK) for critical review of
the manuscript.
Disclosure
The authors report no conflicts of interest in this work.
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